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Individuals with Down syndrome (DS), a genetic condition due to triplication of Chromosome 21, are characterized by intellectual disability that worsens with age. Since impairment of neurogenesis and dendritic maturation are very likely key determinants of intellectual disability in DS, interventions targeted to these defects may translate into a behavioral benefit. While most of the neurogenesis enhancers tested so far in DS mouse models may pose some caveats due to possible side effects, substances naturally present in the human diet may be regarded as therapeutic tools with a high translational impact. Linoleic acid and oleic acid are major constituents of corn oil that positively affect neurogenesis and neuron maturation. Based on these premises, the goal of the current study was to establish whether treatment with corn oil improves hippocampal neurogenesis and hippocampus-dependent memory in the Ts65Dn model of DS. Four-month-old Ts65Dn and euploid mice were treated with saline or corn oil for 30 days. Evaluation of behavior at the end of treatment showed that Ts65Dn mice treated with corn oil underwent a large improvement in hippocampus-dependent learning and memory. Evaluation of neurogenesis and dendritogenesis showed that in treated Ts65Dn mice the number of new granule cells of the hippocampal dentate gyrus and their dendritic pattern became similar to those of euploid mice. In addition, treated Ts65Dn mice underwent an increase in body and brain weight. This study shows for the first time that fatty acids have a positive impact on the brain of the Ts65Dn mouse model of DS. These results suggest that a diet that is rich in fatty acids may exert beneficial effects on cognitive performance in individuals with DS without causing adverse effects. [ABSTRACT FROM AUTHOR]

Down syndrome (DS) is characterized by brain hypotrophy and intellectual disability starting from early life stages. Accumulating evidence shows that the phenotypic features of the DS brain can be traced back to the fetal period since the DS brain exhibits proliferation potency reduction starting from the critical time window of fetal neurogenesis. This defect is worsened by the fact that neural progenitor cells exhibit reduced acquisition of a neuronal phenotype and an increase in the acquisition of an astrocytic phenotype. Consequently, the DS brain has fewer neurons in comparison with the typical brain. Although apoptotic cell death may be increased in DS, this does not seem to be the major cause of brain hypocellularity. Evidence obtained in brains of individuals with DS, DS-derived induced pluripotent stem cells (iPSCs), and DS mouse models has provided some insight into the mechanisms underlying the developmental defects due to the trisomic condition. Although many triplicated genes may be involved, in the light of the studies reviewed here, DYRK1A, APP, RCAN1 and OLIG1/2 appear to be particularly important determinants of many neurodevelopmental alterations that characterize DS because their triplication affects both the proliferation and fate of neural precursor cells as well as apoptotic cell death. Based on the evidence reviewed here, pathways downstream to these genes may represent strategic targets, for the design of possible interventions. [ABSTRACT FROM AUTHOR]

Cognitive disability is an unavoidable feature of Down syndrome (DS), a genetic disorder due to the triplication of human chromosome 21. DS is associated with alterations of neurogenesis, neuron maturation and connectivity that are already present at prenatal life stages. Recent evidence shows that pharmacotherapies can have a large impact on the trisomic brain provided that they are administered perinatally. Epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, performs many actions in the brain, including inhibition of DYRK1A, a kinase that is over-expressed in the DS brain and contributes to the DS phenotype. Young adults with DS treated with EGCG exhibit some cognitive benefits, although these effects disappear with time. We deemed it extremely important, however, to establish whether treatment with EGCG at the initial stages of brain development leads to plastic changes that outlast treatment cessation. In the current study, we exploited the Ts65Dn mouse model of DS in order to establish whether pharmacotherapy with EGCG during peak of neurogenesis in the hippocampal dentate gyrus (DG) enduringly restores hippocampal development and memory performance. Euploid and Ts65Dn mice were treated with EGCG from postnatal day 3 (P3) to P15. The effects of treatment were examined at its cessation (at P15) or after one month (at P45). We found that at P15 treated trisomic pups exhibited restoration of neurogenesis, total hippocampal granule cell number and levels of pre- and postsynaptic proteins in the DG, hippocampus and neocortex. However, at P45 none of these effects were still present, nor did treated Ts65Dn mice exhibit any improvement in hippocampus-dependent tasks. These findings show that treatment with EGCG carried out in the neonatal period rescues numerous trisomy-linked brain alterations. However, even during this, the most critical time window for hippocampal development, EGCG does not elicit enduring effects on the hippocampal physiology. [ABSTRACT FROM AUTHOR]

Background The objective of this study was to assess the fate at long term of mild-to-moderate functional tricuspid regurgitation (TR) left untreated at the time of mitral valve repair in patients with dilated cardiomyopathy. Methods We selected from our prospective hospital database 84 patients (age, 64 ± 9.6 years; ejection fraction, 0.31 ± 0.064) who underwent mitral repair for secondary mitral regurgitation in whom concomitant mild-to-moderate TR (nonlinear scale 1 to 4+) was left untreated. Tricuspid regurgitation was classified as mild in 61 patients (72.6%) and moderate in 23 patients (27.3%). Annular dilatation itself was not systematically measured and was not used as a trigger for tricuspid annuloplasty. Most of the patients were in New York Heart Association functional class III or IV (56 of 84; 66.7%). Results At a median follow-up of 7.3 years (interquartile range, 4.5 to 9.3), 17 patients (20.2%) had moderate-to-severe TR and 21 patients (25%) showed a progression of at least two grades of their untreated preoperative TR. Freedom from moderate-to-severe TR or from progression of at least two grades of the baseline TR was 77% ± 5% at 5 years and 56.7% ± 8.4% at 10 years. Multivariate analysis identified preoperative right ventricular dysfunction (hazard ratio, 7.2; 95% confidence interval, 2.8 to 23; p = 0.001) and age (hazard ratio, 1; 95% confidence interval, 1.0 1.1; p = 0.03) as independent predictors of TR worsening. Conclusions A significant number of dilated cardiomyopathy patients with mild-to-moderate TR left untreated at the time of mitral repair show important TR at follow-up. In this setting, a more aggressive policy should be used taking into consideration the degree of annular dilatation and the function of the right ventricle and not simply the grade of TR. [ABSTRACT FROM AUTHOR]

Background: Limited real-world data comparing outcomes after transcatheter (TAVR) and surgical aortic valve replacement (SAVR) in intermediate-surgical-risk patients with aortic stenosis are available. Methods: We identified 182 consecutive patients who underwent TAVR via the transfemoral (TF) route (November 2007–February 2011) and 111 moderate-to-high-risk historical case controls undergoing SAVR (August 2003–July 2008). Using propensity score matching based on clinical characteristics and surgical risk scores, we compared clinical outcomes in 111 matched patients. Valve Academic Research Consortium definitions were applied for end point adjudication. Results: Baseline clinical characteristics, in particular Logistic European System for Cardiac Operative Risk Evaluation (23.2 ± 15.1 vs 24.4 ± 13.4) and Society of Thoracic Surgeons score (4.6 ± 2.3 vs 4.6 ± 2.6), were well matched between groups. Transfemoral TAVR was associated with more vascular complications (33.3% vs 0.9%, P < .001). On the other hand, acute kidney injury was more frequent after SAVR (8.1% vs 26.1%, P < .001). The rates of all-cause mortality in both TF-TAVR and SAVR groups was1.8% at 30 days (P = 1.00) and 6.4% and 8.1%, respectively, at 1 year (P = .80). At 1 year, the rate of cerebrovascular events was similar in the 2 groups (4.6% vs 9.1%, P = .19). Conclusions: In this real-world cohort of intermediate-surgical-risk patients with aortic stenosis, TF-TAVR and SAVR were associated with similar mortality rates during follow-up but with a different spectrum of periprocedural complications. Furthermore, the survival rate after TF-TAVR in this group of elderly patients with intermediate Society of Thoracic Surgeons score was encouraging. [Copyright &y& Elsevier]